H3K27me3

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H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation of lysine 27 on histone H3 protein.

Contents

This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions. [1]

Nomenclature

H3K27me3 indicates trimethylation of lysine 27 on histone H3 protein subunit:

Abbr.Meaning
H3H3 family of histones
Kstandard abbreviation for lysine
27position of amino acid residue

(counting from N-terminus)

me methyl group
3number of methyl groups added

Lysine methylation

Methylation of lysine.svg

This diagram shows the progressive methylation of a lysine residue. The tri-methylation (right) denotes the methylation present in H3K27me3.

Understanding histone modifications

The genomic DNA of eukaryotic cells is wrapped around special protein molecules known as histones. The complexes formed by the looping of the DNA are known as chromatin. The basic structural unit of chromatin is the nucleosome: this consists of the core octamer of histones (H2A, H2B, H3 and H4) as well as a linker histone and about 180 base pairs of DNA. These core histones are rich in lysine and arginine residues. The carboxyl (C) terminal end of these histones contribute to histone-histone interactions, as well as histone-DNA interactions. The amino (N) terminal charged tails are the site of the post-translational modifications, such as the one seen in H3K27me3. [2] [3]

Mechanism and function of modification

The placement of a repressive mark on lysine 27 requires the recruitment of chromatin regulators by transcription factors. These modifiers are either histone modification complexes which covalently modify the histones to move around the nucleosomes and open the chromatin, or chromatin remodelling complexes which involve movement of the nucleosomes without directly modifying them. [4] These histone marks can serve as docking sites of other co-activators as seen with H3K27me3. This occurs through polycomb mediated gene silencing via histone methylation and chromodomain interactions. A polycomb repressive complex (PRC); PRC2, mediates the tri-methylation of histone 3 on lysine 27 through histone methyl transferase activity. [5] This mark can recruit PRC1 which will bind and contribute to the compaction of the chromatin. [6]

The inflammatory transcription factor NF-κB can cause demethylation of H3K27me3 via Jmjd3 . [7]

H3K27me3 is linked to the repair of DNA damages, particularly repair of double-strand breaks by homologous recombinational repair. [8]

Relationship with other modifications

H3K27 can undergo a variety of other modifications. It can exist in mono- as well as di-methylated states. The roles of these respective modifications are not as well characterised as tri-methylation. PRC2 is however believed to be implicated in all the different methylations associated with H3K27me.

H3K27me1 is linked to promotion of transcription and is seen to accumulate in transcribed genes. Histone-histone interactions play a role in this process. Regulation occurs via Setd2-dependent H3K36me3 deposition. [9]

H3K27me2 is broadly distributed within the core histone H3 and is believed to play a protective role by inhibiting non-cell-type specific enhancers. Ultimately, this leads to the inactivation of transcription. [10]

Acetylation is usually linked to the upregulation of genes. This is the case in H3K27ac which is an active enhancer mark. It is found in distal and proximal regions of genes. It is enriched in Transcriptional start sites (TSS). H3K27ac shares a location with H3K27me3 and they interact in an antagonistic manner.

H3K27me3 is often seen to interact with H3K4me3 in bivalent domains . [11] These domains are usually found in embryonic stem cells and are pivotal for proper cell differentiation. H3K27me3 and H3K4me3 determine whether a cell will remain unspecified or will eventually differentiate. [12] [13] The Grb10 gene in mice makes use of these bivalent domains. Grb10 displays imprinted gene expression. Genes are expressed from one parental allele while simultaneously being silenced in the other parental allele. [14] Demethylation of H3K27me3 can lead to up-regulation of genes controlling the senescence-associated secretory phenotype (SASP). [7]

Other well characterised modifications are H3K9me3 as well as H4K20me3 which—just like H3K27me3—are linked to transcriptional repression via formation of heterochromatic regions. Mono-methylations of H3K27, H3K9, and H4K20 are all associated with gene activation. [15]

Epigenetic implications

The post-translational modification of histone tails by either histone modifying complexes or chromatin remodelling complexes are interpreted by the cell and lead to complex, combinatorial transcriptional output. It is thought that a Histone code dictates the expression of genes by a complex interaction between the histones in a particular region. [16] The current understanding and interpretation of histones comes from two large scale projects: ENCODE and the Epigenomic roadmap. [17] The purpose of the epigenomic study was to investigate epigenetic changes across the entire genome. This led to chromatin states which define genomic regions by grouping the interactions of different proteins and/or histone modifications together. Chromatin states were investigated in Drosophila cells by looking at the binding location of proteins in the genome. Use of ChIP-sequencing revealed regions in the genome characterised by different banding. [18] Different developmental stages were profiled in Drosophila as well, an emphasis was placed on histone modification relevance. [19] A look in to the data obtained led to the definition of chromatin states based on histone modifications. [20] Certain modifications were mapped and enrichment was seen to localize in certain genomic regions. Five core histone modifications were found with each respective one being linked to various cell functions.

The human genome was annotated with chromatin states. These annotated states can be used as new ways to annotate a genome independently of the underlying genome sequence. This independence from the DNA sequence enforces the epigenetic nature of histone modifications. Chromatin states are also useful in identifying regulatory elements that have no defined sequence, such as enhancers. This additional level of annotation allows for a deeper understanding of cell specific gene regulation. [21]

Cause-and-effect relationship between sperm-transmitted histone marks and gene expression and development is in offspring and grandoffspring. [22]

Clinical significance

H3K27me3 is believed to be implicated in some diseases due to its regulation as a repressive mark.

Cohen-Gibson syndrome

Cohen-Gibson syndrome is a disorder linked to overgrowth and is characterised by dysmorphic facial features and variable intellectual disability. In some cases, a de novo missense mutation in EED was associated with decreased levels of H3K27me3 in comparison to wild type. This decrease was linked to loss of PRC2 activity. [23]

Diffuse midline Glioma

Immunohistochemical comparison of DMG with EHZIP overexpression (top) to DMG with H3K27M mutation (bottom). Loss of M3K27me3 (left) is visible in both samples, while H3K27M (middle) and EZHIP (right) only stain in one of the samples, respectively. EZHIP expression in diffuse midline gliomas.webp
Immunohistochemical comparison of DMG with EHZIP overexpression (top) to DMG with H3K27M mutation (bottom). Loss of M3K27me3 (left) is visible in both samples, while H3K27M (middle) and EZHIP (right) only stain in one of the samples, respectively.

Diffuse midline glioma, H3K27me3-altered (DMG), also known as diffuse intrinsic pontine glioma (DIPG) is a type of highly aggressive brain tumor mostly found in children. All DMGs exhibit loss of H3K27me3, in about 80% of cases due to a genetic mutation receplacing lysine with methionine (M), known as H3K27M. In rare forms, H3Kme3-loss is mediated by overexpression of the EZH inhibiting protein, decreasing PRC2-activity. [24]

Spectrum disorders

There is evidence that implicates the downregulation of expression of H3K27me3 in conjunction with differential expression of H3K4me3 AND DNA methylation may play a factor in Fetal Alcohol Spectrum Disorder (FASD) in C57BL/6J mice. This histone code is believed to affect the peroxisome associated pathway and induce the loss of the peroxisomes to ameliorate oxidative stress. [25]

Methods

The histone mark H3K27me3 can be detected in a variety of ways:

1. Chromatin Immunoprecipitation Sequencing (ChIP-sequencing) measures the amount of DNA enrichment once bound to a targeted protein and immunoprecipitated. It results in good optimization and is used in vivo to reveal DNA-protein binding occurring in cells. ChIP-Seq can be used to identify and quantify various DNA fragments for different histone modifications along a genomic region. [26]

2. Micrococcal Nuclease sequencing (MNase-seq) is used to investigate regions that are bound by well positioned nucleosomes. Use of the micrococcal nuclease enzyme is employed to identify nucleosome positioning. Well positioned nucleosomes are seen to have enrichment of sequences. [27]

3. Assay for transposase accessible chromatin sequencing (ATAC-seq) is used to look in to regions that are nucleosome free (open chromatin). It uses hyperactive Tn5 transposon to highlight nucleosome localisation. [28] [29] [30]

See also

Related Research Articles

<span class="mw-page-title-main">Histone</span> Protein family around which DNA winds to form nucleosomes

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar modifications such as DNA methylation it is part of the epigenetic code. Histones associate with DNA to form nucleosomes, which themselves bundle to form chromatin fibers, which in turn make up the more familiar chromosome. Histones are globular proteins with a flexible N-terminus that protrudes from the nucleosome. Many of the histone tail modifications correlate very well to chromatin structure and both histone modification state and chromatin structure correlate well to gene expression levels. The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription. For details of gene expression regulation by histone modifications see table below.

<span class="mw-page-title-main">Bivalent (genetics)</span>

A bivalent is one pair of chromosomes in a tetrad. A tetrad is the association of a pair of homologous chromosomes physically held together by at least one DNA crossover. This physical attachment allows for alignment and segregation of the homologous chromosomes in the first meiotic division. In most organisms, each replicated chromosome elicits formation of DNA double-strand breaks during the leptotene phase. These breaks are repaired by homologous recombination, that uses the homologous chromosome as a template for repair. The search for the homologous target, helped by numerous proteins collectively referred as the synaptonemal complex, cause the two homologs to pair, between the leptotene and the pachytene phases of meiosis I.

<span class="mw-page-title-main">EZH2</span> Protein-coding gene in the species Homo sapiens

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.

Bivalent chromatin are segments of DNA, bound to histone proteins, that have both repressing and activating epigenetic regulators in the same region. These regulators work to enhance or silence the expression of genes. Since these regulators work in opposition to each other, they normally interact with chromatin at different times. However, in bivalent chromatin, both types of regulators are interacting with the same domain at the same time. Bivalent chromatin domains are normally associated with promoters of transcription factor genes that are expressed at low levels. Bivalent domains have also been found to play a role in developmental regulation in pluripotent embryonic stems cells, gene imprinting and cancer.

<span class="mw-page-title-main">PRC2</span>

PRC2 is one of the two classes of polycomb-group proteins or (PcG). The other component of this group of proteins is PRC1.

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.

H3K27ac is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates acetylation of the lysine residue at N-terminal position 27 of the histone H3 protein.

H3K9me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 9th lysine residue of the histone H3 protein and is often associated with heterochromatin.

H3K9me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 9th lysine residue of the histone H3 protein. H3K9me2 is strongly associated with transcriptional repression. H3K9me2 levels are higher at silent compared to active genes in a 10kb region surrounding the transcriptional start site. H3K9me2 represses gene expression both passively, by prohibiting acetylation as therefore binding of RNA polymerase or its regulatory factors, and actively, by recruiting transcriptional repressors. H3K9me2 has also been found in megabase blocks, termed Large Organised Chromatin K9 domains (LOCKS), which are primarily located within gene-sparse regions but also encompass genic and intergenic intervals. Its synthesis is catalyzed by G9a, G9a-like protein, and PRDM2. H3K9me2 can be removed by a wide range of histone lysine demethylases (KDMs) including KDM1, KDM3, KDM4 and KDM7 family members. H3K9me2 is important for various biological processes including cell lineage commitment, the reprogramming of somatic cells to induced pluripotent stem cells, regulation of the inflammatory response, and addiction to drug use.

H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono-methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers.

H3K36me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 36th lysine residue of the histone H3 protein and often associated with gene bodies.

H3K79me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 79th lysine residue of the histone H3 protein. H3K79me2 is detected in the transcribed regions of active genes.

H4K20me is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the mono-methylation at the 20th lysine residue of the histone H4 protein. This mark can be di- and tri-methylated. It is critical for genome integrity including DNA damage repair, DNA replication and chromatin compaction.

H3K14ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 14th lysine residue of the histone H3 protein.

H3K9ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 9th lysine residue of the histone H3 protein.

H3K36me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 36th lysine residue of the histone H3 protein.

H3K36me is an epigenetic modification to the DNA packaging protein Histone H3, specifically, the mono-methylation at the 36th lysine residue of the histone H3 protein.

H3R42me is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the mono-methylation at the 42nd arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

References

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